Numerous correlations have been made which implicate elevated levels of plasma lipoproteins, hyperlipoproteinemia, in the pathogenesis of atherosclerosis. One such disorder, familial hypercholesterolemia, has received special study because of its easy identification and its high morbidity. Patients with this disorder have xanthelasmas, tendon xanthomas, and premature atherosclerosis. The defect responsible for the increased levels of serum cholesterol carried in the low density lipoproteins has not been fully explained. A defect in LDL catabolism has been defined but lipoprotein synthetic alterations may also be present. To investigate lipoprotein synthesis in the hypercholesterolemic state we have been using as an animal model, the cholesterol fed rat. Through studies on the nascent hepatic Golgi lipoproteins from hypercholesterolemic (HC) rats, we have shown that the HC rat liver synthesizes a cholesteryl ester rich VLDL and a lipoprotein similar to plasma LDL. Since LDL have been thought to arise from the catabolism of VLDL, the latter finding may partially explain the increased levels of LDL in the HC rat. We now propose to study the relationship of these nascent lipoproteins to the plasma lipoproteins to determine if the HC liver Golgi LDL is a precursor to plasma LDL. We also propose to study intestinal lipoprotein synthesis. Our studies on lipoprotein synthesis will also be extended to human tissue as it becomes available. The Golgi apparatus from normal human liver and small intestine will be isolated and the associated lipoproteins retrieved and characterized. The nascent human liver and gut lipoproteins will be compared to circulating human plasma lipoproteins.